Wednesday, February 5, 2025
2/5/2025
PROJECT ABSTRACT Natural products continue to have a disproportionate impact on how we understand and treat disease. These biologically pre-validated therapeutic leads have inspired ~50% of FDA-approved drugs, a fact underscores the importance of studying biogenic chemotypes with unique activity in cell culture. Inspired by the rich opportunities for natural products at the interface of chemistry, biology, and medicine, this proposal focuses on a family of terpenoids distinguished by a fused [5-8-5] carbocyclic molecular framework. The flagship members of this family possess impactful, albeit divergent, pharmacological profiles. For example, fusicoccin A stabilizes 14-3-3 protein- protein interactions (PPIs), ophiobolin A is a cytotoxic membrane disruptor, and bipolarolide A inhibits HMG-CoA reductase. The specificity of these terpenoids for their diverse biological receptors is determined by the identity and arrangement of substituents surrounding a common 5-8-5 substructure. Given the complex conformational dynamics of cyclooctanoids, we postulate that the groups flanking the central eight-membered ring modulate the overall molecular shape. This potentially programmable feature might allow this terpenoid family to interface with diverse biological receptors. Thus, the [5-8-5] ring system appears to be a privileged scaffold for the design of novel therapeutics. However, existing approaches to this family of terpenoids rely on convergent, target-specific chemistry. Viewed through the lens of drug discovery, the lack of chemistry to diversify the [5-8-5] motif is the main impediment to understanding and advancing the pharmacology of this natural product family. During the past grant period, we developed a synthetic platform to prepare and edit the fusicoccin scaffold. We now seek to extend this chemistry in several directions. In Aim 1, we will exploit our platform to establish the features of fusicoccin A that impart selectivity for individual 14-3-3 PPIs. In doing so, we bring a unique chemical perspective to the long-standing problem of selectively modulating the 14-3-3 interactome. In Aim 2, we will extend our synthetic strategy to capture ophiobolin A and bipolarolide A. These isomeric sesterterpenes feature peripheral and skeletal modifications to the 5-8-5 scaffold that cannot be addressed by existing chemistry. We outline an enabling synthetic entry point to these molecules from a common 5-8-5 intermediate. Thus, successful completion of the proposed research will establish a divergent platform to chemically redesign [5-8-5] terpenoid chemotypes. It will also establish whether the fusicoccins can be exploited to interrogate specific components of the 14-3-3 interactome in cell culture. This research will signifyingly broaden access to [5-8-5] terpenoid natural products with diverse pharmacological profiles and shed light on how to chemically evolve this chemotype toward a specific functional endpoint.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).